More than 80% of people with type 2 diabetes mellitus (DM2), are obese. Yet, most obese people do not develop diabetes. A critical unsolved question is, what distinguishes obese individuals who are diabetes-resistant from those who are susceptible to diabetes? We have replicated the obesity/diabetes dichotomy in mice by studying an obese diabetes-resistant strain, C57BL/6 ob/ob (B6-ob) and an obese diabetes-susceptible congenic strain, BTBR.ob. We mapped three gene loci (termed t2dm1, t2dm2 &t2dm3) that control diabetes susceptibility in an F2 derived from these progenitors. The objective of this project is to positionally clone the genes underlying these quantitative trait loci (QTL) and identify their role in DM2 susceptibility. During the current grant period, we positionally cloned the locus underlying t2dm2, a locus associated with disrupted islet morphology and reduced insulin secretion in vivo. We narrowed the t2dm2 locus to a 242-kb interval comprising the promoter, one exon, and the first intron of the SorCS1 gene. We studied two different human populations to test the hypothesis that SorCS1 plays a role in diabetes susceptibility in humans. We found association of SorCS1 SNPs with plasma insulin, insulin secretion in a Mexican-American cohort in Los Angeles selected for the absence of diabetes but the presence of metabolic syndrome traits. We also found association of SorCS1 SNPs with age of onset of diabetes and diabetes risk in a Mexican-American cohort in San Antonio. The aims of this proposal are to create a beta-cell-specific SorCS knockout mouse, to positionally clone the remaining two gene loci, t2dm1 and t2dm3. In addition, we shall test the hypothesis that the SorCS1 gene plays a role in islet angiogenesis. We shall identify genetic variants of the SorCS1 gene in our two Mexican-American cohorts and test these variants for binding to several ligands and for their ability to promote angiogenesis in vitro.